Taxol, an antineoplastic agent originally isolated from Taxus brevifolia, is approved for usage in the treatment of ovarian cancer and is expected to see usage in breast, lung, and skin cancers as well. However, since Taxol possesses an extremely low water solubility, i.e., less than 1.5.times.10.sup.-6 molar, it has been necessary to formulate Taxol in a mixture of Cremaphor.TM., a polyoxyethylated castor oil, and ethanol in order to achieve a therapeutic concentration. This formulation can induce a variety of significant side effects including hypersensitivity reactions.
While premedication and slow administration of the drug can circumvent these problems in the clinic, the entire protocol is quite cumbersome and requires extensive close monitoring of patients. Although taxol's dramatic efficacy has driven clinical usage forward despite these problems, a water soluble form of taxol could completely obviate the need for this troublesome protocol.
One approach to bypassing these formulation difficulties, previously attempted by several groups including our own, is the introduction of solubilizing functionality that normal metabolic pathways could remove in vivo. Compounds of this type, termed prodrugs, consist, in the case of taxol, primarily of ester derivatives at the 2' and 7 positions. Currently none of these protaxols have given success in the clinic. In each case, the prodrug is rapidly cleared from circulation by the kidneys.
Taxol is only one of a class of taxo-diterpenoids having bioactivity. Another preferred taxo-diterpenoid having clinically significant activity is Taxotere.TM.. Unfortunately, all known bioactive taxo-diterpenoids have a low aqueous solubility.
What is needed is a method for chemically switching taxol and other taxo-diterpenoids between a high solubility and low solubility form in a manner which regulates its rate of clearance from circulation so that the prodrug is retained for a clinically significant period after administration.
Taxol itself is known to serve as a chemical switch with respect to tubulin. Binding of taxol to tubulin prevents its polymerization and the formation of microtubules. While unpolymerized tubulin is soluble in aqueous media, polymerization of tubulin leads to the formation of insoluble microtubules. Accordingly, the addition or removal of taxol drives the depolymerization or polymerization of tubulin and, in this manner, serves as a chemical switch for regulating the solubility of tubulin.